POSSIBLE MECHANISM FOR THE ANTIATHEROSCLEROTIC ACTION OF THE CALCIUM-CHANNEL BLOCKER AE0047 IN CHOLESTEROL-FED RABBITS

1, The present study was designed to investigate the antiatherosclerot ic effect of AE0047, a calcium channel blocker, and to compare it with that of nilvadipine in cholesterol-fed rabbits, Furthermore, the effe cts of AE0047 on low-density lipoprotein (LDL) oxidation were studied in vitro, 2, A 7 week treatment period with AE0047 (3 and 10 mg/kg, p. o.) led to a dose-dependent reduction in the lipid deposition area by Oil Red-O staining (surface index) without affecting serum lipid level s, There was no reduction in the surface index following treatment wit h the same dose of nilvadipine (10 mg/kg),3, In a vehicle-administered high-fat diet group of rabbits, levels of total cholesterol (TC) and esterified cholesterol (EC) and calcium content in the aorta were incr eased approximately two-to three-fold over those of the normal diet gr oup, Increased levels of TC and EC and calcium content were reduced to the same levels as the normal diet group by AE0047 treatment, whereas nilvadipine did not affect TC and EC levels, 4, In an in vitro study, AE0047 (10 mu mol/L) inhibited LDL oxidation and the aggregation of a polipoprotein (Ape) B-100 induced by Cu2+, Furthermore, AE0047 inhibit ed the degradation of oxidized LDL by macrophages. In contrast, the sa me dose of nilvadipine (10 mu mol/L) did not inhibit either LDL oxidat ion or the aggregation of ApoB-100, 5, In summary, AE0047 inhibited LD L oxidation, resulting in a decrease of its uptake into macrophages an d an inhibition of cholesterol esterification. This leads to an anti-a therosclerotic effect of AE0047, Thus, AE0047 may have therapeutic pot ential in preventing cardiovascular disease in hypertensive patients.